A longstanding interest of the Chess lab is the study of
unusual mechanisms involved in regulating gene expression. Recently we have
been developing approaches to allow the study of epigenetic regulation at the
scale of the entire human genome. Understanding of epigenetic mechanisms is
essential to understanding normal development and disease. The Chess Lab
website will have more information (http://research.mssm.edu/chesslab/
).
DNA Methylation
DNA methylation stands out amongst epigenetic marks in that
it is a covalent modification of the DNA molecule itself (albeit a modification
that doesn’t change the DNA sequence). For DNA methylation (specifically
methylation of cytosines within CpG dinucleotides) there is a known mechanism
for replicating the mark. The DNA methyltransferase I encodes a protein which
recognizes hemi-methylated DNA (arising from the replication of a
double-stranded methylated DNA molecule) and methylates the other strand. Genome-scale
analyses of DNA methylation have led to the first demonstration of methylation
of the gene body (the entire transcribed region) of mammalian genes. This work
also showed more methylation on the active X than the inactive X in female
cells (Hellman and Chess, 2007). These observations resulted from our decision
to consider all types of CpGs rather than earlier studies that focused on CpG
islands. Gene body methylation, which is present in plant genomes as well as
animal genomes, adds another layer of complexity to the role of DNA methylation
in regulation of the genome.
Polymorphism in DNA sequence is well known, but until
recently the potential for DNA methylation polymorphism was not explored. We
and others have found evidence for such DNA methylation polymorphism. Our
genome-scale analyses have revealed an interesting interplay between DNA
sequence polymorphism and DNA methylation polymorphism (Hellman and Chess,
2010).
Random monoallelic expression
Monoallelic expression represents a good model system for
studying epigenetics because it requires the differential treatment of two
alleles (which are sometimes identical in sequence). Monoallelic expression
with random choice between the maternal and paternal alleles defines an unusual
class of genes comprising X-inactivated genes and a few autosomal
gene-families. Using a genome-wide approach, a few years ago we assessed
allele-specific transcription of ~4,000 human genes in clonal cell lines and
found that over 300 were subject to random monoallelic expression (Gimelbrant
et al., 2007). For a majority of monoallelic genes, they observed some clonal
lines displaying biallelic expression. Clonal cell lines reflect an independent
choice to express the maternal, the paternal, or both alleles for each of these
genes. This can lead to differences in expressed protein sequence, and to
differences in levels of gene expression.
Widespread monoallelic expression suggests a mechanism that
generates diversity in individual human cells and their clonal descendants. We
have extended these observations to the mouse genome (in preparation, 2011).
Some other highlights
Discovery of allelic exclusion of mouse odorant receptor
genes (Chess et al., 1996).
Identification of the odorant receptor gene family in Drosophila,
along with the demonstration that different olfactory neurons express different
receptors and converge in their projections to the antennal lobe creating a
spatial representation of olfactory space (Gao and Chess, 1999; Gao et al.,
2000).
Elucidation of a role for asynchronous replication in
immunoglobulin gene allelic exclusion (Mostoslavsky et al., 2001).
Demonstration of chromosome-level coordination of
replication timing in mouse and human cells (Singh et al., 2003; Ensminger and
Chess, 2004).
Cloning of a mouse from an olfactory neuron (Eggan et al.,
2004).
Insights into the evolution of the odorant receptor gene
family in humans (Gimelbrant et al., 2004).
Uncovering a role for alternative splicing in the
specification of unique identity of neurons (Neves et al., 2004; Zhan et al.,
2004).
Discovery of a non-coding RNAs associated with nuclear
structures, and the demonstration that one of them, NEAT1, plays a structural
role in the nuclear parapspeckle (Hutchinson et al., 2007; Clemson et al.,
2009).
